Copyright Statement

Abstract

The resolution and improved synthesis of the naturally occurring, adamantanetype, tetraarsenical (±)-Arsenicin A is reported. The five-step synthesis of (±)-Arsenicin A
from methylenebis(phenylarsinic acid) affords (±)-Arsenicin A as air-stable, colorless crystals
having an mp of 182−184 °C after column chromatography and recrystallization from
benzene (overall yield: 36%). The resolution of (±)-Arsenicin A was achieved by preparative
HPLC on a Chiralpak IA column with the use of dichloromethane as eluent to give both
enantiomers in >99% enantiomeric purity (HPLC); the isolated enantiomers had [α]
58920
=
−60.2 and +62.3 (0.01% NEt3
/CH2
Cl2
). (S)-(−)-Arsenicin A, having an mp of 241−242 °C
from dichloromethane, crystallizes in the space group P21
21
21
with one molecule having the
(S
As,S
As,S
As,S
As) or overall S configuration in the asymmetric unit. The adamantane-type
structure of (±)-Arsenicin A is reminiscent of arsenic(III) oxide (As4
O6
), but where three of
the oxygen atoms in the inorganic oxide have been replaced by methylene groups in a chiral C2
arrangement. ((±)-Arsenicin A, mp 182−184 °C, crystallizes from benzene in the
centrosymmetrical space group P1
̅: the unit cell of the crystal contains two independent
pairs of molecules, the molecules in each pair being related by an inversion center.) The individual enantiomers of (±)-Arsenicin
A racemize in the presence of traces of acid, and high-level ab initio calculations have been performed to examine the mechanism
of the process. (±)-Arsenicin A exhibits a 21-fold greater inhibition of the induction of proliferation arrest and induces cell death
at a 27-fold lower concentration in the acute promyelocytic leukemia cell line than the current "arsenical gold standard",
arsenic(III) oxide (Trisenox). (±)-Arsenicin A is also more potent than arsenic(III) oxide for the induction of proliferation arrest
in two other cancers with particularly bad prognoses: pancreatic adenocarcinoma and glioblastoma.